The present invention relates to laminated elastin, laminated elastin-based biomaterials, and to laminated tropoelastin materials, to methods of producing such laminated materials, and more particularly to methods of using these laminated materials in tissue repair and replacement.
Elastin fibers are responsible for the elastic properties of several tissues such as skin and lung, as well as arteries, and are composed of two morphologically distinct components, elastin and microfibrils. Microfibrils make up the quantitatively smaller component of the fibers and play an important role in elastic fiber structure and assembly.
The most abundant component of elastic fibers is elastin. The entropy of relaxation of elastin is responsible for the rubber-like elasticity of elastic fibers. Elastin is an extracellular matrix protein that is ubiquitous in mammals. Elastin is found, for example, in skin, blood vessels, and tissues of the lung where it imparts strength, elasticity and flexibility. In addition, elastin, which is prevalent in the internal elastic lamina (IEL) and external elastic lamina (EEL) of the normal artery, may inhibit the migration of smooth muscle cells into the intima. Elastin in the form of solubilized peptides has been shown to inhibit the migration of smooth muscle cells in response to platelet-derived factors (Ooyambia et al, Arter iosclerosis 7:593 (1987). Elastin repeat hexapeptides attract bovine aortic endothelial cells (Long et al, J. Cell. Physiol. 140:512 (1989) and elastin nonapeptide s have been shown to attract fibroblasts (U.S. Pat. No. 4,976,734). The present invention takes advantage of these physical and biochemical properties of elastin.
Thirty to forty percent of atherosclerotic stenoses are opened with balloon angioplasty restenose as a result of ingrowth of medial cells. Smooth muscle ingrowth into the intima appears to be more prevalent in sections of the artery where the IEL of the artery is ripped, torn, or missing, as in severe dilatation injury from balloon angioplasty, vessel anastomoses, or other vessel trauma that results in tearing or removal of the elastic lamina. While repair of the arterial wall occurs following injury, the elastin structures IEL and EEL do not reorganize. Since these components play major structural and regulatory roles, their destruction is accompanied by muscle cell migration. There are also diseases that are associated with weakness in the vessel wall that result in aneurysms that can ultimately rupture, as well as other events that are, at least in part, related to abnormalities of elastin.
In vertebrates elastin is formed through the secretion and crosslinking of tropoelastin, the 72-kDa biosynthetic precursor to elastin. This is discussed, for example, in an article entitled xe2x80x9cOxidation, Cross linking, and Insolubilization of Recombinant Crosslinked Tropoelastin by Purified Lysyl Oxidasexe2x80x9d by Bedell Hogan, et al in the Journal of Biological Chemistry, Vol. 268, No. 14, on pages 10345 10350 (1993).
In vascular replacement and repair, the best current option is to implant autologous veins and arteries where the obvious limit is the supply of vessels which can be sacrificed from the tissues they were intended to service. Autologous vein replacements for damaged arteries also tend to be only a temporary measure since they can deteriorate in a few years in high pressure arterial circulation.
When autologous graft material is not available, a surgeon must choose between sacrificing the vessel, and potentially the tissue it sub-served, or replacing the vessel with synthetic materials such as Dacron or Gore tex. Intravascular compatibility indicate that several xe2x80x9cbiocompatible polymersxe2x80x9d, including Dacron, invoke hyperplastic response, with inflammation particularly at the interface between native tissue and the synthetic implant. Incomplete healing is also due, in part, to a compliance mismatch between currently used synthetic biomaterials and native tissues.
As described in the prior co-pending patent applications assigned to the assignees of this application set forth above (patent application Ser. No. 08/798,426 filed Feb. 7, 1997, Ser. No. 08/797,770 filed Nov. 19, 1998, Ser. No. 08/798,425 filed Feb. 7, 1997, Ser. No. 09/000,604 filed Dec. 30, 1997, and U.S. Pat. No. 5,989,244, issued Nov. 23, 1999, and U.S. Pat. No. 5,990,379 issued Nov. 23, 1999) all of which are incorporated herein by reference, elastin and elastin-based biomaterials, or tropoelastin materials, can be used in a number of medical applications. For example, these materials can be employed to provide a method of effecting repair or replacement or supporting a section of a body tissue, as a stent, such as a vascular stent, or as conduit replacement, or as an artery, vein or a ureter replacement, or as a stent or conduit covering or coating or lining. It can also provide a graft suitable for use in repairing a lumen wall, or in tissue replacement or repair in, for example, interior bladder replacement or repair, intestine, tube replacement or repair such as fallopian tubes, esophagus such as for esophageal varicies, ureter, artery such as for aneurysm, vein, stomach, lung, heart such as congenital cardiac repair, or colon repair or replacement, or skin repair or replacement, or as a cosmetic implantation or breast implant.
Surgical repair of major injury to the duodenum for example, with significant tissue los, requires innovative surgical techniques, and is associated with significant morbidity and mortality. Segmental resection and primary end to end anastomosis is not possible in this region due to its close proximity to the head of pancreas, and connections with common bile duct and pancreatic duct. Small defects can be repaired by primary closure, which will result in stricture of the duodenum depending on the amount of tissue loss. Large defects cannot be repaired this way. It will require innovative techniques, such as creation of a Jejunal patch, duodenojejunostomy, serosal onlay patch, pyloric exclusion with gastrojejunostomy, or even pancreatico duodenectomy. The last procedure is fairly extensive, and is not likely to be tolerated by acutely injured patients with other multiple injuries. The first three procedures can be done, but they still require long surgery time involving additional bowel anastomosis, and are feasible only when the jejunum is intact. Pyloric exclusion is accompanied by prolonged external drainage of the duodenal content, which makes it difficult to manage fluid and electrolyte balance, and high incidence of intraabdominal infection, sepsis and chronic fistula formation, predisposing the victim to prolonged intensive care, parenteral nutrition, hospitalization, and disability. This is due to the high content of electrolyte and digestive enzymes in the duodenal fluid, which comes mainly from bile and pancreatic excretion. As a result, prolonged leakage of duodenal content is associated with prolonged and extensive tissue loss and sepsis. Recent development in antibiotics and intensive care has significantly reduced the mortality rate from this condition but morbidity is still high.
The use of the subject laminated elastin and/or elastin based biomaterials and/or tropoelastin materials, typically in the form of a heterograft, which can employ a biodegradable glue or adhesive material, and which can be used for repair of defects such described above with respect to the duodenom. The elastin and/or elastin-based biomaterials and/or tropoelastin, in laminated form, can be used to provide a reliable barrier to repair or replace a tissue substrate, typically injured or diseased human tissue. The subject biodegradable glue provides quick and easy water tight tissue fusion between the laminated materials and the tissue substrate.
A technique has been developed that can easily, quickly, and reliably repair the injury to organs, such as the duodenum, without compromising the lumen. It should result in a much faster recovery with less complications, morbidity, and mortality. The laminated elastin and/or elastin based biomaterials and/or tropoelastin can be used to repair such defect without compromising the lumen. Also, in the case of the duodenum there is no need for other bowel anastomosis, or extensive resection. This laminated material was shown to be biologically inert, inducing minimal immunological response, and to be resistant to infection, and hydrochloric acid.
More specifically, a method is provided herein for producing the above-described laminated elastin or laminated elastin-based materials or laminated tropoelastin materials. The laminated elastin or laminated elastin-based materials or laminated tropoelastin materials is capable of being attached to a tissue substrate for repair or replacement thereof. The tissue substrate can comprise either a human or animal tissue.
The method comprises the steps of providing at least one layer of unlaminated elastin or unlaminated elastin-based materials or unlaminated tropoelastin materials. Then, the unlaminated elastin or unlaminated elastin-based materials or unlaminated tropoelastin materials is subjected to heating and pressing steps. The pressing step of the present invention is preferably conducted in the presence of steam. Preferably, depending on the thickness and nature of the unlaminated material and the desired laminated material final properties, the preferred pressure applied is from about 40 psi up to about 2000 psi, and the preferred temperature during pressing is from about 50 degrees C. up to about 170 degrees C.
The laminated elastin or laminated elastin-based materials or laminated tropoelastin materials preferably comprises a multi-layer composite material. More preferably, the laminated elastin or laminated elastin-based materials or laminated tropoelastin materials are bilaminar pressed materials.
Typically, the step of adhering with an adhesive material the laminated elastin or laminated elastin-based materials or laminated tropoelastin materials is employed in order to achieve a water-tight engagement with the tissue substrate. A biogradable cyanacrylate glue is generally used in order to achieve quick and easy way to secure the patch in place and provide watertight fusion instantly. Preferably, the adhesive material comprises a cyanoacrylate material. More preferably, the cyanoacrylate material comprises an alkoxy alkyl cyanoacrylate material.
The method of this invention can also include the step of suturing the laminated elastin or laminated elastin-based materials or laminated tropoelastin materials to the tissue substrate. Preferably, the suturing step is affected without substantial tearing of the laminated elastin or laminated elastin-based materials or laminated tropoelastin materials.
Further objects and advantages of the invention will be clear from the description that follows.